Poor Sleep May Signal Onset of Alzheimer's

Disturbed sleep quality may be an early sign of Alzheimer's disease, researchers reported.

Action Points

Disturbed sleep quality may be an early sign of Alzheimer's disease.

Note that another study found that levels of both beta-amyloid trimers and beta-amyloid*56 increased with age, but in the cognitively intact older adults, the levels were elevated in individuals at risk for Alzheimer's disease.

Disturbed sleep quality may be an early sign of Alzheimer's disease, researchers reported.

In a cross-sectional study among cognitively normal people, deposition in the brain of a molecule involved in Alzheimer's pathogenesis was associated with poor sleep efficiency, according to David Holtzman, MD, of Washington University School of Medicine in St. Louis.

On the other hand, deposition of beta-amyloid -- regarded as the earliest identifiable stage of Alzheimer's -- was not associated with lack of sleep, Holtzman and colleagues reported online in JAMA Neurology.

Sleep/wake disturbances are common in Alzheimer's, the researchers noted, but it's not known if they precede any cognitive impairment. To try to clarify that issue, they studied 142 cognitively normal people, ages 45 and older, taking part in long-term studies of memory and aging.

The researchers used actigraphy for 2 weeks to obtain an objective measurement of both sleep efficiency – the proportion of time in bed spent asleep -- and total sleep time.

And they measured levels of beta-amyloid42 in the cerebrospinal fluid (CSF) to determine whether amyloid deposition was taking place, with a level of less than 500 picograms per milliliter indicating "strong likelihood for amyloid deposition."

Of the participants, 32 (22.5%) had CSF levels of the molecule that indicated beta-amyloid deposition in the brain, the authors reported.

Those 32 had worse sleep quality than other participants (80.4% versus 83.7%) as measured by an average sleep efficiency. After the researchers corrected for age, sex, and APOEε4 allele carrier status, the difference was significant (P=0.04).

A second measure of sleep quality -- wake time after sleep onset -- was also higher in those with signs of beta-amyloid deposition at 63.1 minutes versus 54 minutes (P=0.045).

On the other hand, total sleep time was not significantly different, at 401.3 minutes on average in the deposition group compared with 403 minutes on average among the other participants.

The habit of taking frequent naps -- defined as napping on 3 or more days a week -- was also linked with amyloid deposition: 31.2% of the deposition group and 14.7% of the other participants were frequent nappers (P=0.03).

Holtzman and colleagues cautioned that they did not assess participants using other markers of amyloid deposition, such as imaging. As well, they noted, the study was exploratory and only assessed a small number of variables.

Nonetheless, they argued, the findings should stimulate future research that will, among other things, guide the direction of the relationship between sleep and amyloid deposition.

If it turns out that sleep disruption increases the risk of Alzheimer's, they argued, it would provide "an even stronger motivation to identify and treat individuals with sleep disorders, such as obstructive sleep apnea."

A second study in the journal also examined biomarkers in the cerebrospinal fluid in relation to the risk of Alzheimer's.

Their goal was to assess the molecular basis of early pathophysiology and to see how beta-amyloid is involved. Specifically, they hypothesized that two beta-amyloid oligomers -- beta-amyloid trimers and beta-amyloid*56 -- were pathogenic.

In animal studies, beta-amyloid*56 has been associated with loss of cognition. It is also thought to be composed of four beta-amyloid trimers.

The researchers measured CSF levels of beta-amyloid trimers and beta-amyloid*56, as well as the 42-amino acid beta-amyloid isoform, total tau and phospho-tau 181.

The latter three are currently regarded as CSF biomarkers for the preclinical stages of Alzheimer's, Ashe and colleagues noted.

They found that levels of both beta-amyloid trimers and beta-amyloid*56 increased with age, but in the cognitively intact older adults, the levels were elevated in individuals at risk for Alzheimer's disease.

They also showed "stronger relationships" than did the 42-amino acid beta-amyloid isoform, which is a surrogate for beta-amyloid fibril deposition.

On the other hand, the strong correlations were weaker among the impaired group, a finding that is "interesting in light of the failure of experimental (beta-amyloid) therapies" to improve mild cognitive impairment or Alzheimer's, the authors wrote.

"Knowing which (beta-amyloid) species to target in asymptomatic subjects may enhance the success of future treatments," they concluded.

The study by Holtzman's group had support from the NIH, the Ellison Medical Foundation, Fred Simmons and Olga Mohan, and the National Center for Research Resources. Holtzman reported no conflicts of interest.

The study by Ashe's group had support from the NIH and the Swedish Research Council. The journal said the authors reported no conflicts of interest.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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